Neurotrophic factors have a profound influence on developmental events such as naturally occurring cell death, differentiation and process outgrowth (Snider, 1989). The brain-derived neurotrophic factor (BDNF) is a neurotrophic factor which belongs to the neurotrophin family of growth factors. BDNF acts on certain neurons of the central nervous system (CNS) and the peripheral nervous system (PNS), helping to support the survival of existing neurons and encourage the growth and differentiation of new neurons and synapses (Acheson, 1995; Huang, 2001). Increasing BDNF has been associated with the treatment of a number of disorders including Parkinson's disease, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), depressive disorders, retinitis pigmentosa, erectile dysfunction, memory disorders, Rett syndrome; Alzheimer's Disease, bipolar disorder and acute mania.
Parkinson's disease is a chronic and progressive degenerative disease of the brain that impairs motor control, speech, and other functions. One of the most striking features of Parkinson's disease is that it primarily affects a restricted neuronal population in the brain. Although other neurons are also affected, the dopaminergic neurons of the substantia nigra pars compacta are the most vulnerable to the disease process (Chesselet, 2003). BDNF has potent effects on survival and morphology of mesencephalic dopaminergic neurons, increasing their survival, and thus its loss could contribute to death of these cells in Parkinson's disease (PD) (Hyman, 1991; Howell, 2000).
Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms and by a progressive degeneration of neurons in basal ganglia in brain cortex. Patients suffering from HD have significantly lower BDNF levels in serum compared to healthy controls (Ciammola, 2007).
Amyotrophic lateral sclerosis (ALS) is a chronic and debilitating neurodegenerative disease which involves degeneration of cortical, bulbar and medullar motor neurons. Riluzole (2-amino-6-[trifluoromethoxy]benzothiazole) is an antagonist of glutamatergic neurotransmission that prolongs survival in ALS (Riviere, 1998). Riluzole has also been shown to significantly increase BDNF levels in the rat brain, thereby promoting precursor proliferation (Katoh-Semba, 2002).
Depression is another indication in which BDNF has been shown to have an effect. In a meta-analysis which encompasses many studies, depressed patients were shown to have lower BDNF levels than healthy control subjects, and anti-depressant therapy has been shown to increase BDNF levels in depressed patients after treatment (Sen, 2008).
Retinitis pigmentosa is a disease associated with retinal photoreceptor cell loss. It has been shown that BDNF culturing of retina explants from rd mice, who suffer from a mutation in the same gene that has been found mutated in human autosomal recessive retinitis pigmentosa, showed an increase in number of photoreceptor nuclei in the outer nuclear layer (Caffe Romeo, 2001). This suggests that increasing BDNF levels in humans suffering from retinitis pigmentosa may slow the progression of the disease.
Erectile dysfunction is another disease which has been shown to be associated with BDNF. In U.S. Pat. No. 7,485,311, example 3, it was shown that treatment of rats in the bilateral cavernous nerve freezing model using intracavernous injection of AAV-BDNF improves maximum intracavernous pressure in response to bilateral cavernous nerve electrostimulation.
BDNF has also been associated with learning and memory. In a transgenic mouse model of BNF knockout mice, impairment of BDNF production has been shown to cause impairments in learning and memory in the adult stage and especially during early development (Monteggia, 2007). In a rat model, it was shown that endogenous BDNF in the hippocampus is involved in memory formation. Whereas infusion of function-blocking anti-BDNF antibody was shown to impair short term and long term memory in a model of fear-motivated learning, infusion of recombinant human BDNF facilitated long-term memory retention (Alonsa, 2005). Increasing BDNF levels in human patients in need of learning or memory improvement may also improve short and long term memory.
Rett Syndrome (RTT) is an X-linked neurodevelopmental disorder and the leading cause of severe mental retardation in females, affecting 1:10,000-15,000 births worldwide (Amaral, 2007). The disease is associated with mutations in the gene MeCP2. One of the targets of MeCP2 is the BDNF gene. This suggests that deregulation of BDNF expression in Rett Syndrome may be the cause of structural anomalies observed in patients, especially the reduced dendritic branching and loss of dendritic spines (Amaral, 2007). This suggests that increasing BDNF levels in Rett syndrome may be a viable therapy in treating the disease.
In bipolar disorder patients suffering from acute mania, levels of BDNF were shown to vary depending upon whether the patient was treated or untreated. Before treatment with known mania treatments, BDNF levels were found to be lower than in healthy controls, but upon treatment, the difference between BDNF levels in serum of treated patients and controls was no longer significant (Tramontina, 2009). It may be possible to treat acute mania by increasing BDNF levels in patients in need thereof.
Several agents have been identified to increase BDNF levels including riluzole and antidepressants such as fluoxetine (Prozac®) (Katoh-Semba, 2002; Molteni, 2006).